Bone Morphogenetic proteins (BMPs) show great promise as bone anabolic agents in several therapeutic settings. One of the most important potential clinical applications is in the treatment of age-related osteoporosis. However, the utility of BMP treatment of age-related osteoporosis and related fractures may be limited by resistance to the bone forming actions of BMPs in the aged skeleton. Thus, understanding the mechanisms of age-related resistance to BMPs is critical to the success of strategies aimed at restoring sensitivity and/or overcoming resistance to bone anabolic action in the aged. Our work and that of others indicates that BMP-2 and BMP-7, the two most widely studied BMPs, stimulate osteoblastic differentiation by activating IGF-1 signaling pathways. However, studies also indicated that osteoprogenitor cells from aged animals may be resistant to the bone anabolic effects of IGF-1 due to reduced IGF-1 stimulated IGF-1 receptor phosphorylation and reduced activation of downstream signaling pathways including PI3K/Akt and ERK. We and others have found that BMP signaling via the PKC isoform PKD may be a component in the IGF-1 signaling pathway that stimulates osteoblastic differentiation. Based on our preliminary studies indicating that bone marrow stromal cells (BMSC) from aged wild-type mice and from young and old IGF-1 receptor heterozygous mice may be resistant to BMP-7, we hypothesize that BMSC from aged mice are resistant to BMP-7 activation of PI3K/Akt/PKD signaling and possibly other IGF-1 signaling pathways. We propose to test this hypothesis by first comprehensively examining the IGF-1R, PI3K/Akt/PKD and ERK pathways for resistance to BMP-7 activation in BMSC from aged mice. We will critically test the hypothesis that resistance of these pathways to BMP-7 stimulation underlies the resistance of BMSC to the differentiating effect of BMP-7 by conducting RNA silencing of the IGF-1R in cells from young wild-type mice and by expressing constitutively active forms of the IGF-1R and downstream effector molecules in cells from aged wild-type and young and aged Igf1r mice and determining whether they can inhibit and promote osteoblastic differentiation, respectively. In our second specific aim we will translate these findings to the in-vivo setting by determining whether young IGF-1 receptor heterozygous mice and old wild-type mice are resistant to the ectopic bone forming action of BMP-7. We will also determine whether IGF-1 receptor haplo-insufficiency exacerbates age-related resistance to BMP-7 induced bone formation. Successful outcomes will provide the basis for future studies designed to rescue in vivo age-related resistance to BMPs by expressing active forms of IGF-1 signaling intermediates. These results could lead to the development of new therapeutic modes for treating osteoporosis. PUBLIC HEALTH RELEVANCE: Age related osteoporosis is a major cause of debilitation and morbidity in the gerontological population. The goal of the current study is to provide a molecular basis for the development of novel therapeutic agents that will treat age related osteoporosis by activating signal transduction pathways used by bone anabolic agents.